The present invention relates generally to the field of site-specific drug delivery, particularly to delivery of drugs to a target organ.
Delivery of drug to a specific treatment site represents a substantial challenge in the design of drug delivery systems. While drugs designed for action at or within a specific organ (e.g., the heart, liver, pancreas, prostate, and the like) may be suitable for systemic delivery, the amount of drug that must be delivered by this route generally must be quite high in order to result in delivery of a therapeutically effective amount at the desired site of action. Delivery of such high amounts of drug increases the likelihood and severity of side effects, and is otherwise disadvantageous, e.g., in terms of cost-effectiveness of therapy. One approach to accomplish site-specific drug delivery involves the use of a catheter, which can be positioned at a treatment site to facilitate localized delivery of drug from a drug reservoir of a drug device (e.g., an external or implanted pump) that may be positioned some distance from the treatment site. However, delivery of agents to a site within an organ generally requires breaking the surface of the organ to implant a catheter tip within the organ. This may be particularly undesirable where the organ is sensitive or already damaged, and may compromise the integrity of structures surrounding the organ.
The heart is an example of an organ of particular interest for organ-specific delivery. The pericardium, or pericardial sac, is a membranous sac in which the heart is contained. The pericardium and the pericardial fluid together function to prevent dilation of the chambers of the heart, to lubricate the surfaces of the heart, and to maintain the heart in a fixed geometric position. The space between the pericardium and the heart, known as the pericardial space, contains the pericardial fluid which bathes the heart.
Delivery of therapeutic agents directly to the pericardial space for treating various cardiac disorders overcomes some of the disadvantages associated with systemic delivery of these agents. For example, systemic dosages sufficient to confer a therapeutic effect on the heart may produce undesired side effects on other organs and tissues of the body. Current methods for accessing the pericardial space require puncturing the pericardial sac to introduce a needle or a catheter. See, for example, U.S. Pat. Nos. 5,931,810; and 5,827,216. Others means of accessing the pericardial space involve the use of an iontophoretic device. See, for example, U.S. Pat. No. 5,634,895. Each of these devices carries with it inherent risks to the pericardium and/or the heart muscle, such as puncturing or mechanically damaging the cardiac tissue, or inducing fibrillation upon application of an electric field.
U.S. Pat. No. 5,387,419 states that a biocompatible polymeric matrix with an incorporated anti-arrhythmic agent can be applied directly to the heart muscle via the epicardium, endocardium, or pericardium. This matrix has limitations in that the drug to be delivered must be integrated into a polymer to form a biocompatible matrix which requires the steps of forming a mixture of the drug and polymer, forming the mixture into a desired shape and curing formed mixture for a period of time. The foregoing steps may be difficult, time consuming and/or require use of catalytic chemicals or high pressure. Furthermore, because the device requires that the drug must be integrated into the polymer, this may limit drug loading (i.e., the amount of drug that can be incorporated into the polymer) which in turn limits the duration and dose of the drug that can be delivered, and in addition, requires that the drug and polymer to be compatible with each other (i.e., drug and polymer must be miscible and not adversely reactive to each other). In addition, because the device requires drug to be integrated into a polymer, it may be relatively more difficult to replenish the drug contained in the patch once such patch is attached to the heart where prolonged delivery of a drug is required (e.g., for the treatment of a chronic disease).
There is a need in the art for improved devices and methods for delivering therapeutic agents directly to or into an organ of interest. The present invention addresses this need by providing an implantable drug delivery patch and drug delivery system.
The present invention features devices and methods for delivery of drug to or into an internal organ by delivery of drug directly to the surface of the organ such that the drug traverses the organ surface and enters the organ tissue. The device is in the form of an implantable drug delivery patch comprising a first layer, which is generally substantially drug-impermeable. When the first layer is placed on an outer surface of an organ, a drug reservoir is defined by the first layer and the organ surface.
In some embodiments, the patch further comprises a second layer, which, when the patch is placed onto an outer surface of an organ, is disposed between the organ surface and the first layer. In these embodiments, the second layer comprises a drug-permeable membrane, and a drug reservoir is defined by the first layer and the drug-permeable membrane of the second layer.
The patch is held in place on the organ surface with an attachment element, which can be part of the first layer or, if present, the second layer, or can be a separate component which is attached to the first layer or the second layer, and is adjacent the delivery surface.
The patch is useful for delivering a wide variety of therapeutic agents and thus is useful in treating various conditions, and is also useful for systemic delivery of a therapeutic agent. The implantable drug delivery patch of the invention is advantageous in that the drug can be delivered to the organ without disrupting or compromising any organ structure, e.g., by puncturing or subjecting to an electrical field. The patch of the invention can also be used in patients who do not have organs with intact sacs surounding the organ to which drug is to be delivered.
In some embodiments, the patch of the invention is refillable. In some of these embodiments, refilling is achieved by accessing the patch with a catheter or a needle which provides a conduit from a drug delivery device or a drug source at a distal site. Thus, an advantage of this embodiment of the drug delivery patch of the invention is that it can be refilled. The refillable feature of the patch confers a number of advantages in that the need to replace the patch is avoided; the volume rate of delivery can be controlled; and the concentration gradient of the drug across the organ surface can be maintained.
A further advantage of the patch of the invention is conferred by the first layer, which, in those embodiments in which the first layer is substantially impermeable to body fluids, protects the drug contained in the reservoir from interaction with body fluids outside the organ. This is particularly advantageous when drugs that are sensitive to molecules in body fluids, such as enzymes, are being delivered. In addition to protecting the drug from degradation, the first layer can also be made to be drug-impermeable, so as to prevent or reduce dilution of the drug contained within the reservoir, and may limit drug loss to the environment surrounding the target organ.
A further advantage is that the patch of the invention may further comprise a second layer comprising a material having properties that allow a controlled drug delivery rate, thus providing better dosing control.
The invention further provides a drug delivery system comprising a patch of the invention, a catheter, and a distal drug delivery device. The drug delivery device may be a convective delivery device, e.g., suitable for low volume rate delivery.
Another advantage of the invention is that the effective dose of drug can be lower since drug is delivered to a localized, or regional, treatment site at the organ of interest, thus avoiding or mitigating the adverse side effects of such drugs when administered systemically in doses sufficient to be efficacious.
A further advantage of the invention is that the patch can be adapted for consistent, continuous, dosing of a therapeutic agent.
These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the invention as more fully described below.